Characterization of Bronchodilator Response in Children With Bronchiolitis Using Phenotypic and Genotypic Features

Обзор

Bronchiolitis is the leading cause of pediatric morbidity and healthcare costs. Despite the commonplace use of bronchodilator treatments, like albuterol, in conditions like asthma, their efficacy in bronchiolitis remains controversial due to the heterogeneity in patient response. Although studies indicate that bronchodilators do not enhance outcomes in bronchiolitis, meta-analyses can obscure the heterogeneity of treatment effects. While bronchodilator response genetics have not been explored in bronchiolitis, treatment effectiveness variations often depend on genomic factors. Genome-wide association studies (GWAS) have linked genetic variants with bronchodilator response and outcomes in childhood asthma, suggesting a bronchodilator-responsive genotype. This proposal aims to extend this paradigm to bronchiolitis, addressing the gap in knowledge where GWAS and clinical characteristics intersect. The proposed study's objective is to characterize phenotypic and genotypic variations of children with bronchiolitis and their association with bronchodilator response. We hypothesize that children with bronchiolitis who exhibit clinical and historical characteristics associated with atopy and specific physical findings have genetic variants linked to bronchodilator response. To achieve this, we propose to (Aim 1) define airway responsiveness to bronchodilator treatment in children with bronchiolitis using the change in respiratory score, (Aim 2a) identify the associations between candidate genetic variants and bronchodilator response among children with bronchiolitis, and (Aim 2b) determine the associations between candidate genetic variants and clinical patient data to identify bronchodilator-responsive children with bronchiolitis. A prospective, double-blind, randomized, placebo-controlled trial of a single albuterol dose in children aged 3 to 24 months presenting with bronchiolitis to the emergency department will be conducted to achieve these aims. Patient information and respiratory assessment outcomes will be collected before and after intervention. Blood, urine, DNA buccal swabs, and nasopharyngeal swabs will also be collected. Completion of these aims will result in a novel clinical prediction model for bronchodilator response determination in bronchiolitis, integrating clinical, physical, and genetic data. Furthermore, this research supports the candidates' career development goals of advancing training in clinical trial research design and execution and becoming an expert in clinical and translational methods to enhance pediatric emergency department health and outcomes. Ultimately, this work will inform an R01 application to validate an evidence-based prediction rule for identifying bronchodilator-responsive children with bronchiolitis through a multi-center emergency medicine research network, optimizing therapeutic approaches, and reducing resource use in those with a low likelihood of bronchodilator response.

Вмешательства

• Препарат Albuterol Sulfate, 2.5 Mg/3 mL (0.083%) Inhalation Solution
  Children with bronchiolitis will be randomized to an intervention arm to be administered as a nebulization (albuterol sulfate 2.5mg/ 3mL inhalation solution). The intervention drug will be placed in a sealed manila envelope, randomized in advance by a Nemours Investigational Drug Pharmacist, and stored in the ED pyxis.
• Препарат Sodium Chloride 0.9% Inhl 3Ml
  Children with bronchiolitis will be randomized to an intervention arm to be administered as a nebulization (sodium chloride 0.9% 3mL inhalation solution). The intervention drug will be placed in a sealed manila envelope, randomized in advance by a Nemours Investigational Drug Pharmacist, and stored in the ED pyxis.

Первичные конечные точки

• Minimum Clinically Important Difference (Aim 1) [Срок оценки: Immediately after the intervention]
• Candidate genetic variants (Aim 2) [Срок оценки: through study completion, an average of 1 year]

Критерии участия

Критерии включения

• Children between 3 to 24 months of age
• Clinical diagnosis of bronchiolitis by the treating provider(s), defined by the American Academy of Pediatrics as a clinical syndrome involving lower respiratory tract symptoms
• Children who either have no history of prematurity or have a history of prematurity but without associated co-morbidities
• Emergency department (ED) visit to seek care at Nemours Children's Health-Florida (NCH-FL)

Критерии исключения

• Patients previously enrolled in the PI's K12 study
• Documented history of asthma or reactive airway disease
• Co-morbidities affecting airway response (e.g., chronic lung disease, bronchopulmonary dysplasia, bronchiectasis, congenital heart disease, immunodeficiency, neurologic condition)
• Diagnosis of pneumonia by chest radiography
• Inhaled, nebulized, or oral corticosteroid use within 72 hours of ED evaluation
• Inhaled, nebulized, or oral bronchodilator administration within 4 hours of ED arrival

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Nemours Children's Health — Orlando

Публикации

• McCulloh RJ, Smitherman SE, Koehn KL, Alverson BK. Assessing the impact of national guidelines on the management of children hospitalized for acute bronchiolitis. Pediatr Pulmonol. 2014 Jul;49(7):688-94. doi: 10.1002/ppul.22835. Epub 2013 Jul 19. PMID 23868897
• Knapp JF, Simon SD, Sharma V. Variation and trends in ED use of radiographs for asthma, bronchiolitis, and croup in children. Pediatrics. 2013 Aug;132(2):245-52. doi: 10.1542/peds.2012-2830. Epub 2013 Jul 22. PMID 23878045
• Willson DF, Horn SD, Hendley JO, Smout R, Gassaway J. Effect of practice variation on resource utilization in infants hospitalized for viral lower respiratory illness. Pediatrics. 2001 Oct;108(4):851-5. doi: 10.1542/peds.108.4.851. PMID 11581435
• Gong C, Byczkowski T, McAneney C, Goyal MK, Florin TA. Emergency Department Management of Bronchiolitis in the United States. Pediatr Emerg Care. 2019 May;35(5):323-329. doi: 10.1097/PEC.0000000000001145. PMID 28441240
• Viswanathan M, King VJ, Bordley C, Honeycutt AA, Wittenborn J, Jackman AM, Sutton SF, Lohr KN. Management of bronchiolitis in infants and children. Evid Rep Technol Assess (Summ). 2003 Jan;(69):1-5. No abstract available. PMID 12624885
• Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev. 2014 Jun 17;2014(6):CD001266. doi: 10.1002/14651858.CD001266.pub4. PMID 24937099
• Ralston SL, Lieberthal AS, Meissner HC, Alverson BK, Baley JE, Gadomski AM, Johnson DW, Light MJ, Maraqa NF, Mendonca EA, Phelan KJ, Zorc JJ, Stanko-Lopp D, Brown MA, Nathanson I, Rosenblum E, Sayles S 3rd, Hernandez-Cancio S; American Academy of Pediatrics. Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics. 2014 Nov;134(5):e1474-502. doi: 10.1542/ PMID 25349312
• Pelletier AJ, Mansbach JM, Camargo CA Jr. Direct medical costs of bronchiolitis hospitalizations in the United States. Pediatrics. 2006 Dec;118(6):2418-23. doi: 10.1542/peds.2006-1193. PMID 17142527

Идентификаторы

NCT: NCT06946264 · 1866573

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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